Activation of p38 mitogen-activated protein kinase and c-Jun NH2- terminal kinase by double-stranded RNA and encephalomyocarditis virus: Involvement of RNase L, protein kinase R, and alternative pathways

Mihail S. Iordanov, Jayashree M. Paranjape, Aimin Zhou, John Wong, Bryan R G Williams, Eliane F. Meurs, Robert H. Silverman, Bruce E. Magun

Research output: Contribution to journalArticle

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Abstract

Double-stranded RNA (dsRNA) accumulates in virus-infected mammalian cells and signals the activation of host defense pathways of the interferon system. We describe here a novel form of dsRNA-triggered signaling that leads to the stimulation of the p38 mitogen-activated protein kinase (p38 MAPK) and the c-Jun NH2-terminal kinase (JNK) and of their respective activators MKK3/6 and SEK1/MKK4. The dsRNA-dependent signaling to p38 MAPK was largely intact in cells lacking both RNase L and the dsRNA-activated protein kinase (PKR), i.e., the two best-characterized mediators of dsRNA-triggered antiviral responses. In contrast, activation of both MKK4 and JNK by dsRNA was greatly reduced in cells lacking RNase L (or lacking both RNase L and PKR) but was restored in these cells when introduction of dsRNA was followed by inhibition of ongoing protein synthesis or transcription. These results are consistent with the notion that the role of RNase L and PKR in the activation of MKK4 and JNK is the elimination, via inhibition of protein synthesis, of a labile negative regulator(s) of the signaling to JNK acting upstream of SEK1/MKK4. In the course of these studies, we identified a long- sought site of RNase L-mediated cleavage in the 28S rRNA, which could cause inhibition of translation, thus allowing the activation of JNK by dsRNA. We propose that p38 MAPK is a general participant in dsRNA-triggered cellular responses, whereas the activation of JNK might be restricted to cells with reduced rates of protein synthesis. Our studies demonstrate the existence of alternative (RNase L- and PKR-independent) dsRNA-triggered signaling pathways that lead to the stimulation of stress-activated MAPKs. Activation of p38 MAPK (but not of JNK) was demonstrated in mouse fibroblasts in response to infection with encephalomyocarditis virus (ECMV), a picornavirus that replicates through a dsRNA intermediate. Fibroblasts infected with EMCV (or treated with dsRNA) produced interleukin-6, an inflammatory and pyrogenic cytokine, in a p38 MAPK-dependent fashion. These findings suggest that stress-activated MAPKs participate in mediating inflammatory and febrile responses to viral infections.

Original languageEnglish (US)
Pages (from-to)617-627
Number of pages11
JournalMolecular and Cellular Biology
Volume20
Issue number2
DOIs
StatePublished - Jan 2000

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Encephalomyocarditis virus
Double-Stranded RNA
JNK Mitogen-Activated Protein Kinases
RNA Viruses
p38 Mitogen-Activated Protein Kinases
Protein Kinases
eIF-2 Kinase
2-5A-dependent ribonuclease
Fibroblasts
Picornaviridae
Proteins
Virus Diseases
Interferons
Antiviral Agents
Interleukin-6

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Activation of p38 mitogen-activated protein kinase and c-Jun NH2- terminal kinase by double-stranded RNA and encephalomyocarditis virus : Involvement of RNase L, protein kinase R, and alternative pathways. / Iordanov, Mihail S.; Paranjape, Jayashree M.; Zhou, Aimin; Wong, John; Williams, Bryan R G; Meurs, Eliane F.; Silverman, Robert H.; Magun, Bruce E.

In: Molecular and Cellular Biology, Vol. 20, No. 2, 01.2000, p. 617-627.

Research output: Contribution to journalArticle

Iordanov, Mihail S. ; Paranjape, Jayashree M. ; Zhou, Aimin ; Wong, John ; Williams, Bryan R G ; Meurs, Eliane F. ; Silverman, Robert H. ; Magun, Bruce E. / Activation of p38 mitogen-activated protein kinase and c-Jun NH2- terminal kinase by double-stranded RNA and encephalomyocarditis virus : Involvement of RNase L, protein kinase R, and alternative pathways. In: Molecular and Cellular Biology. 2000 ; Vol. 20, No. 2. pp. 617-627.
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